Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1.alpha., MIP-1.beta., the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or "CKR-1" or "CC-CKR-1") [MIP-1.alpha., MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2B" or "CC-CKR-2A"/"CC-CKR-2B") [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MIP-1.alpha., RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or "CKR-5" OR "CC-CKR-5") [MIP-1.alpha., RANTES, MIP-1.beta.] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or "CKR-6" or "CC-CKR-6") [LARC] (Baba et al., J. Biol. Chem.", 272, 14893-14898 (1997)); CCR-7 (or "CKR-7" or "CC-CKR-7") [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or "CKR-8" or "CC-CKR-8") [I-309, TARC, MIP-1.beta.] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or "CKR-10" or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: ##STR2##
wherein R.sub.1 is C.sub.1-6 alkyl, optionally substituted with functional groups such as --NR.sup.6 CONHR.sup.7, wherein R.sup.6 and R.sup.7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 98/31364 describes disubstituted piperidines which are useful as modulators of chemokine receptors: ##STR3##
wherein R.sup.1 is benzylpiperidine or benzylpyrrolidine. Such disubstituted piperidines are not considered part of the present invention.
WO 96/26196 is directed to certain benzylpiperidines and piperazines as muscarinic antagonists: ##STR4##
In these compounds as well as other muscarinic antagonists, the ring of R.sup.2 is linked directly to the piperidine containing Y and Z. The compounds of the present invention do not include compounds of this type.
WO 95/19344 discloses tachykinin antagonists of formula: ##STR5##
wherein X is O or NR.sup.19, R.sup.1 and R.sup.2 are substituted phenyl, and R.sup.3 may be COR.sup.9, CONR.sup.10 R.sup.11 and the like. Such compounds require this substitution at R.sup.1, R.sup.2, and X while R.sup.3 groups do not represent those of the present invention.
Other tachykinin antagonists include those of WO 97/22597, in which the two piperidine or pyrroline rings must be linked directly through a bond: ##STR6##
U.S. Pat. No. 5,576,319 discloses a method of treatment for schizophrenia comprising administering a compound of formula: ##STR7##
to a patient in need thereof. These compounds are not indicated as modulators of CCR3, and do not contain the necessary features of the present invention.
WO 97/06802 concerns oxido-squalene cyclase inhibitors of formula: ##STR8##
and WO 98/35959 concerns similar heterocyclic derivatives of formula: ##STR9##
wherein T.sub.1, T.sub.2, and T.sub.3 may be carbon or nitrogen, X may be methylene, Q is a carbocyclic ring, A may be absent and G is N or CH. Such compounds contain pyridine or pyridine derivatives directly off the piperidine rings. Further, the compounds of these references which bridge the pyridine analogously to the present invention require a carbonyl functionality in the linker.
Sulphonamide derivatives are implicated in WO 97/48681 as useful in the treatment of CNS disorders. The nitrogen bearing R.sup.1 and R.sup.2 of compounds of formula: ##STR10##
may be taken together to form a piperidine ring, however, such rings may only be substituted when an additional nitrogen is contained in the ring formed by R.sup.1 and R.sup.2.
The foregoing reference compounds are readily distinguished structurally by either the nature of the terminal functionality, attachment chain, or possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidines and pyrrolidines as having activity toward the chemokine receptors.